Search

Das Kapitel behandelt, ausgehend von der WHO-Klassifikation, die ganze Pathologie der soliden und zystischen Tumoren des Pankreas mit Ausnahme der neuroendokrinen Neoplasien, die im Band zur Pathologie des Urogenitale, der endokrinen Organe, der Gelenke und der Knochen zur Sprache kommen. Bei den soliden Tumoren werden umfassend das sporadische und familiare duktale Adenokarzinom (mitsamt seiner PanIN-Vorlauferlasionen), das Azinuszellkarzinom und die solide pseudopapillare Neoplasie besprochen. Bei den zystischen Tumoren stehen die immer wichtiger und wegen ihrer verbesserten radiologischen Identifizierung immer haufiger werdenden intraduktalen Neoplasien an erster Stelle, gefolgt von den muzinos- und seros-zystischen Neoplasien. Den Abschluss bilden seltene und ungewohnliche Neoplasien sowie tumorartige Lasionen wie die autoimmune Pankreatitis. Bei allen Tumoren wird auf die gegenwartigen Therapieformen und Prognoseparameter sowie auf die molekulare Genetik im Hinblick auf die diagnostische Charakterisierung und mogliche therapeutische Bedeutung eingegangen.

Die S3-Pankreaskarzinomleitlinie wurde im letzten Jahr aktualisiert. Neben der internistisch-onkologischen und Palliativtherapie standen die chirurgische Therapie und insbesondere die Pathologie im sog. Themenkomplex 3 zur Aktualisierung an. Die Neuerungen betreffen im Wesentlichen die histopathologische Aufarbeitung, die besonders im Hinblick auf den zirkumferenziellen Resektionsrand und die R-Klassifikation uberarbeitet wurde. Weiterhin wird in den Empfehlungen festgelegt, welche Angaben ein vollstandiger pathohistologischer Befund enthalten sollte. Insbesondere auf die Angabe der Lymphknotenratio wird abgehoben.

Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas - because of their cytological atypia - were recognized as precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression, mainly because hyperplastic polyps lack cytological atypia. Meanwhile, it is evident that the lesions formerly classified as hyperplastic represent a heterogeneous group of polyps, some of which exhibit a significant risk of neoplastic progression. These lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CIMP pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas (SSA), traditional serrated adenomas (TSA) and mixed polyps, showing serrated and "classical" adenomatous features. In a consensus conference of the working group of gastroenterological pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-α (TNF-α) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-α, was inhibited by TNF-α protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-α and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process. (Cancer Res 2006; 66(18): 9045-53)

The increasing application of mammography, mainly in screening programs for the early detection of breast cancer, and the high technical standard of imaging has resulted in the detection of clinically occult breast tumors. Considering that only diagnosis at an early stage will be able to change the prognosis of breast cancer, this diagnostic challenge appears to be the most exciting field in both breast imaging and breast pathology. Especially the precursor lesions need to be diagnosed and defined precisely to understand their prognostic significance. In imaging, the morphologic appearance of precursor lesions is usually neither typical nor pathognomonic. They have to be assessed histologically using percutaneous interventions. Recent molecular studies have demonstrated various genetic alterations in the ductal epithelium, with the earliest onset in atypical ductal hyperplasia. The recent WHO classification, which is based on molecular data and histopathological features, attempts to define in particular the precursor lesions and low grade intraductal carcinomas. The clinical importance of the various grades has to be assessed. Intimate cooperation between diagnostic radiologist and pathologist is essential.

Der wichtigste Vertreter der insgesamt seltenen intraduktalen Tumoren des Pankreas ist die intraduktale papillar-muzinose Neoplasie (IPMN). Dieser Tumor, der erst in den letzten Jahren im Detail beschrieben wurde, ist 1996 in die WHO-Klassifikation aufgenommen worden. Die IPMN zeigen fur lange Zeit ein intraduktales Wachstum, bevor sie in etwa 50% der Falle invasiv werden. Damit grenzen sie sich prognostisch deutlich vom duktalen Adenokarzinom ab. Gegenwartig sind die IPMN die haufigsten zystischen Neoplasien, die reseziert werden. Neue Untersuchungen zeigen, dass die IPMN aufgrund ihres Muzin-Musters in verschiedene Typen mit wahrscheinlich unterschiedlicher Biologie unterteilt werden mussen.

Das duktale Adenokarzinom des Pankreas ist der bei weitem haufigste maligne Pankreastumor. Es gehort zu den Tumoren mit schlechter Prognose. Die morphologischen Charakteristika sind: bevorzugte Lokalisation im Pankreaskopf, duktal-glandulare Tumorstrukturen verbunden mit ausgepragter Desmoplasie und CEA- und MUC1-Positivitat. Varianten dieses Karzinoms sind das adenosquamose Karzinom, das undifferenzierte pleomorphe Karzinom sowie der gemischte duktal-endokrine Tumor. Mit der Definition von Gangveranderungen als pankreatische intraepitheliale Neoplasie (PanIN) konnten ein Progressionsmodell fur die Entstehung des duktalen Pankreaskarzinoms entwickelt und korrespondierende Genalterationen nachgewiesen werden.

Solid pseudopapillary neoplasms (SPN) of the pancreas represent a special tumor entity, both morphologically and biologically. They form large solitary tumors that occur predominantly in young women. Histologically, they show solid, pseudopapillary, and pseudocystic patterns. The tumor cells are monomorphous and typically express vimentin, neuron-specific enolase, nuclear beta-catenin, and the progesterone receptor. Complete resection cures the tumor in about 90% of the cases. However, because recurrences and even metastases may occur in a small number of cases, SPN are classified as low-grade malignant tumors. Predicting malignancy histologically is not yet possible. The most important differential diagnosis to consider is neuroendocrine tumor of the pancreas. The etiology and pathogenesis of SPN are obscure.

S100P is a member of the S100 family of calcium-binding proteins and there have been several recent reports of its overexpression in pancreatic ductal adenocarcinoma (PDAC). We have used Far Western screening and in vitro interaction assays to identify and confirm a novel target protein for S100P. We have named this protein S100PBPR, and shown that its interaction with S100P is dependent on Ca(2+) or Mg(2+). S100PBPR was found to localize to cell nuclei where S100P is also present, and the two proteins co-immunoprecipitate. By in situ hybridization, S100PBPR transcript was found in islet cells but not duct cells of the healthy pancreas. Both S100P and S100PBPR were detected by quantitative real-time polymerase chain reaction in pancreatic intraepithelial neoplasia (PanIN) and PDAC samples, and in situ hybridization revealed the presence of S100PBPR transcript in malignant PDAC cells. These data suggest that an interaction between S100P and S100PBPR may be involved in early pancreatic cancer. S100P was further investigated in PanIN lesions and immunohistochemical analysis showed its expression to correlate significantly with increasing grade of PanINs, being found as early as PanIN-1 with more prevalent expression in PanIN-2 and -3. These data suggest that S100P can be added to the genetic progression model for PDAC.

Autoimmune pancreatitis seems to be a disease with a heterogeneous appearance. Our intention was to establish key diagnostic criteria, define grades of severity and activity, identify features of potential subtypes and evaluate the diagnostic relevance of biopsy specimens.Histopathological criteria and clinical features were recorded in pancreatic resection specimens from 53 patients who were found to have chronic pancreatitis lacking pseudocysts, calculi, irregular duct dilatations, pancreas divisum and/or duodenal wall inflammation. The severity of the chronic inflammation was graded, and the activity of the acute inflammatory component and the granulocytic epithelial lesion (GEL) were determined. Additionally, pancreatic biopsy specimens from 9 patients with suspected AIP were assessed.Periductal lymphoplasmacytic infiltration was identified in all cases, followed in order of frequency by periductal fibrosis and venulitis. These changes were absent in 147 pancreatic specimens that showed chronic pancreatitis associated with pseudocysts, calculi, pancreas divisum and/or duodenal wall inflammation. In 90% of the cases, these chronic changes were graded as 3 or 4. In 81%, the inflammatory process resided in the head of the pancreas and involved the common bile duct. GELs were present in 42% of the patients, who had a mean age of 40.5 years, an almost equal male-female ratio and a high coincidence of ulcerative colitis or Crohn's disease. Patients without GELs were older (mean age 64 years), showed a male preponderance, commonly had Sjogren's syndrome and often developed recurrent bile-duct stenosis. Diagnostically relevant lesions were present in two of five wedge biopsy specimens and three of four fine-needle specimens.Periductal lymphoplasmacytic infiltration and fibrosis, preferential occurrence in the pancreatic head and venulitis characterize autoimmune pancreatitis. GELs predominantly occur in a subset of patients who are younger, more commonly have ulcerative colitis and Crohn's disease and seem to have fewer recurrences than patients without GELs. Pancreatic biopsy material proved to be a very helpful adjunct for establishing the diagnosis.

Gene expression profiling revealed ADAM9 to be distinctly overexpressed in pancreatic ductal adenocarcinoma (PDAC). We examined the relevance of ADAM9 expression in PDAC diagnosis and prognosis. A total of 59 infiltrating PDACs, 32 specimens from patients with chronic pancreatitis, 11 endocrine tumours and 24 acinar cell carcinomas were immunohistochemically analysed for ADAM9 expression. Staining for ADAM9 was detected in 58 out of 59 (98.3%) PDACs and in two out of 24 (8.3%) acinar cell carcinomas, but not in endocrine tumours. In the non-neoplastic pancreas, whether normal or chronically inflamed, ADAM9 was expressed in centroacinar and intralobular duct cells, but not in interlobular duct cells and their hyperplastic lesions. Pancreatic ductal adenocarcinomas showing cytoplasmic ADAM9 expression correlated with poor tumour differentiation and also with shorter overall survival than in cases showing only an apical membranous staining pattern (P=0.001). Multivariate analysis identified cytoplasmic ADAM9 expression as an independent marker of shortened survival in a set of 42 curatively (R0) resected PDAC (P

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

Secretory carcinomas (SCA) are distinguished from infiltrating ductal carcinomas (IDC) of the breast by their characteristic histomorphology and more favorable prognosis and by the expression of a chimeric tyrosine kinase that is encoded by the ETV6-NTRK3 fusion gene. On this basis, we evaluated 13 SCAs (12 of them with ETV6-NTRK3 gene fusion) by molecular and immunohistochemical (IHC) methods. DNA was obtained from 8 of 13 microdissected SCAs and was analyzed for genetic alterations (GA) by comparative genomic hybridization (CGH). IHC staining was performed for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67 (MIB1) in all 13 cases. Molecular and immunohistochemical results in SCAs were compared with previous data regarding immunohistochemical and molecular characteristics of IDCs. An average of 2.0 GAs (range: 0 to 6) were detected, including recurrent gains of chromosome 8q (37.5%) and 1q (25%) and losses of 22q (25%). Four of 13 (31%) SCAs were positive for ER, and 2 were positive for PR. The mean MIB1-labeling index was 11.4% (range

BACKGROUND Pancreatic ductal adenocarcinomas (PDACs) are extremely rare before age 40 years. The objective of the current study was to determine whether the features of PDACs in patients age < 40 years differ from those in older patients. The authors reviewed the literature and their own files. METHODS The cases reported in the literature were evaluated to determine their precise diagnoses and characteristic features. In a series of 439 PDACs from the authors' files, tumors in patients age 40 years. RESULTS Of 71 pancreatic carcinomas reported in patients age 40 years in their pathologic and molecular findings. Three patients were age ≤ 20 years, and 2 of those patients had a mucinous component with MUC2 positivity. CONCLUSIONS The incidence of PDACs in patients age 40 years, but they seemed to include more variants, particularly mucinous carcinomas. In addition, PDACs in younger patients frequently appeared to be associated with genetic factors. Cancer 2004;100:173–82. © 2003 American Cancer Society

Background: Unicystic ameloblastomas (UAs) and dentigerous cysts (DCs) have an identical clinical and radiographic appearance. Some subtypes of UAs have a better prognosis than solid or multicystic ameloblastomas, and simple enucleation is the adequate treatment. The present study was designed to test the hypothesis that UAs with small islands of ameloblastomatous epithelium may be misdiagnosed as a DC or keratocyst if no more than two histologic sections are examined. Methods: A total of 101 resection specimens from 22 women and 73 men (mean age: 46.5 years) were selected, all showing the clinical and radiographic features of a DC. Only cysts with a minimum diameter of 15 mm in the panoramic X-ray were considered for the present investigation. The histopathologic diagnosis had been routinely established by examining two sections. For our study, the specimens were investigated by step sections at 50 µm and by staining of 5 µm thin sections with hematoxylin and eosin (H&E) at 1 mm levels. An average of 15 slides were evaluated per case. Results: Microscopic examination of the step sections did not reveal ameloblastomatous epithelium in the cyst lining epithelium of the 101 cases. Thus, every primary diagnosis of a dentigerous cyst was confirmed. In four cases, additional rather large odentogenic cell nests were detected with palisading of basaloid cells, while there was a lack of other signs of ameloblastic differentiation. All lesions were completely resected, and no additional treatment was performed. Conclusions: Step sectioning of larger DCs may reveal associated odontogenic cell nests in some cases but does not lead to the detection of formerly missed ameloblastic cells. Thus, unicystic ameloblastomas are not misdiagnosed if only two slides are prepared for routine diagnosis of DCs.

Pancreatic mucinous noncystic (colloid) carcinomas (MNCC) differ from the usual ductal adenocarcinomas in their mucin expression profile and share with many extrapancreatic mucinous carcinomas the expression of MUC2. Because mucinous carcinomas are frequently associated with mutations of the DNA mismatch repair genes, causing them to exhibit the so-called mutator phenotype, we decided to investigate whether MNCCs of the pancreas are characterized by microsatellite instability (MSI). Twelve carcinomas with a mucinous phenotype (8 mucinous noncystic carcinomas, 3 intraductal papillary-mucinous carcinomas with an invasive muconodular component, and 1 ductal adenocarcinoma with an extensive mucinous noncystic component) and 11 ductal adenocarcinomas were immunostained with monoclonal antibodies to the mismatch repair gene products hMLH1, hMSH2, and hMSH6. For MSI analysis, DNA was isolated from microdissected tissue, and five primary microsatellites (BAT 25, BAT 26, D5S346, D17S250, and D2S123) were analyzed. MSI was diagnosed in case a novel allele was found, compared with the normal tissue. The criterion for LOH was a 75% signal reduction. All carcinomas tested exhibited nuclear expression of mismatch repair gene products, except for one MNCC that also showed MSI at the molecular level. The data suggest that pancreatic carcinomas with a mucinous phenotype (MUC2+/MUC1-) do not appear to normally exhibit mutations in the mismatch repair genes and therefore differ in their carcinogenesis from those in other organs.

Die Diagnostik der Barrett-Schleimhaut und ihrer verschiedenen Grade der intraepithelialen Neoplasie (fruher: Dysplasie) gilt in mehreren Aspekten als schwierig. Auf einer Konsensus-Konferenz der Arbeitsgemeinschaft "Gastroenterologische Pathologie der Deutschen Gesellschaft fur Pathologie" wurde daher versucht eine Standardisierung der histopathologischen Diagnostik in folgenden Punkten zu erarbeiten: Diagnostik und Terminologie der Barrett-Mukosa, Abgrenzung der Barrett-Mukosa von der intestinalen Metaplasie der Kardia, diagnostische Kriterien der intraepithelialen Neoplasie, Anzahl der zu entnehmenden Biopsien sowie Wertigkeit zusatzlicher immunhistologischer und/oder molekularbiologischer Methoden. Abschliesend wurde eine Empfehlung zur Einholung einer "zweiten Meinung" bei intraepithelialer Neoplasie formuliert.

Intraductal tubulopapillary neoplasms of the pancreas are very rare tumors characterized by intraductal tubulopapillary growth, ductal differentiation, scant intracellular mucin production and cellular dysplasia. Here, we report the first case of an intraductal tubulopapillary neoplasm of the pancreas with clear cell morphology. The tumor was detected during the diagnostic work-up of acute pancreatitis in a 43- year old female. Histological examination revealed a tumor with the typical architecture of an intraductal tubulopapillary neoplasm of the pancreas with tumor cells showing abundant clear cytoplasm and Di-PAS negativity. Immunohistochemistry revealed positivity for Pan-CK, CK7, CK8/18, MUC1, MUC6, carbonic anhydrase IX, CD10, EMA, β-catenin and e-cadherin. Sanger sequencing did not detect mutations for β-catenin, BRAF, KRAS, PIK3CA and GNAS. Altogether, histology, immunohistochemical expression profile (MUC1+, MUC6+, MUC2-, MUC5AC-, thrypsin-, chymotrypsin-, CDX2-) and sequencing results led to the diagnosis of intraductal tubulopapillary neoplasm. However, the neoplasm consisted of cells showing abundant clear cytoplasm, a morphological pattern not being described so far in the current classification of pancreatic intraductal neoplasms. Potential differential diagnosis and the molecular basis of clear cell morphology are discussed. In conclusion, we consider this tumor as intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype. After surgery and without adjuvant therapy, the patient’s clinical course has been uneventful for over two years now. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1051828790117127

Intraductal papillary-mucinous neoplasms of the pancreas seem to comprise various types, whose relationship to ductal adenocarcinoma and mucinous noncystic carcinoma is unclear. We analyzed the mucin immunophenotype and the DPC4/SMAD4 expression in intraductal papillary-mucinous neoplasms, ductal carcinomas, and mucinous noncystic carcinomas to define features that may help to distinguish between different types of intraductal papillary-mucinous neoplasms and to establish their relationship to other neoplasms of the exocrine pancreas. A series of 51 intraductal papillary-mucinous neoplasms, three mucinous noncystic carcinomas (two with an intraductal component), and 35 ductal adenocarcinomas were screened immunohistochemically for their expression of MUC1, MUC2, MUC5, and DPC4/SMAD4. All intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas were positive for MUC5. Thirty-two intraductal papillary-mucinous neoplasms and three mucinous noncystic carcinomas abundantly expressed MUC2 but no (or only little) MUC1. The remaining intraductal papillary-mucinous neoplasms showed either mainly MUC1 expression or focal MUC1 and MUC2 expression. All ductal carcinomas but one were MUC2 negative and MUC1 and MUC5 positive. DPC4 was not expressed in two intraductal papillary-mucinous neoplasms that showed a tubular invasion pattern. Twelve of 23 ductal adenocarcinomas were DPC4 positive. Intraductal papillary-mucinous neoplasms can be divided into at least three different mucin immunophenotypes. The first and largest group of intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas is MUC1 negative and MUC2 positive and probably forms one tumor entity. The second group seems to be related to ductal carcinoma because of its MUC1 positivity in the absence or very weak MUC2 staining. The third group shows focal MUC1/MUC2 expression and is characterized by oncocytic histology.

The presumed precursor lesions of pancreatic ductal adenocarcinoma were recently classified according to their increasing grade of dysplasia and were designated as pancreatic intraepithelial neoplasia (PanIN) 1 through 3. In this study, we tested whether molecular genetic alterations can be correlated with this classification and may help to further categorize the various PanIN grades. We determined the frequencies of allelic loss at chromosomal arms 9p, 17p, and 18q in 81 microdissected duct lesions of various PanIN grades, using a combination of whole genome amplification and microsatellite analysis. In addition we examined the p53 and Dpc4 protein expression patterns by immunohistochemical analysis. In PanIN-1, we did not detect allelic losses. In PanIN-2, allelic losses were found in increasing frequency, and were particularly high in those lesions with moderate-grade dysplasia (low grade, 20, 33, and 17%, loss at 9p, 17p, and 18q, respectively; moderate grade, 46, 77, and 58%). PanIN-3 and invasive carcinomas exhibited abundant losses. Abnormal p53 and Dpc4 protein expression was only rarely identified in PanIN-2 lesions, but occurred frequently in PanIN-3 lesions and invasive carcinomas. The combined genetic and protein expression data support a model in which allelic loss is the first hit in the biallelic inactivation of the p53 and DPC4 tumor suppressor genes. In addition, our data indicate that allelic loss analysis may be useful in separating PanIN-2 lesions with low-grade dysplasia from those PanIN-2 lesions with moderate-grade dysplasia, each potentially representing a distinct progression step toward invasive carcinoma.

Smad4/ DPC4 (deleted in pancreatic carcinoma, locus 4) is a tumor suppressor gene lost at high frequency in cancers of the pancreas and other gastrointestinal organs. Smad4 encodes a key intracellular messenger in the transforming growth factor β (TGF-β) signaling cascade. TGF-β is a potent inhibitor of the growth of epithelial cells; thus, it has been assumed that loss of Smad4 during tumor progression relieves this inhibition. Herein, we show that restoration of Smad4 to human pancreatic carcinoma cells suppressed tumor formation in vivo , yet it did not restore sensitivity to TGF-β. Rather, Smad4 restoration influenced angiogenesis, decreasing expression of vascular endothelial growth factor and increasing expression of thrombospondin-1. In contrast to the parental cell line and to control transfectants that produced rapidly growing tumors in vivo , Smad4 revertants induced small nonprogressive tumors with reduced vascular density. These data define the control of an angiogenic switch as an alternative, previously unknown mechanism of tumor suppression for Smad4 and identify the angiogenic mediators vascular endothelial growth factor and thrombospondin-1 as key target genes.

The purpose of this study was to evaluate the influence of regional versus extended lymphadenectomy on survival after partial pancreaticoduodenectomy for pancreatic cancer. From October 1988 to December 1991 (Department of Surgery, University of Hamburg) and from January 1992 to March 1998 (Department of Surgery, University of Kiel) 72 patients with histologically proven ductal adenocarcinoma of the pancreatic head were treated. Partial pancreaticoduodenectomy with regional lymphadenectomy was performed in 26 patients. In 46 patients lymphadenectomy was expanded to include extended retroperitoneal lymphatic and connective tissue clearance. Comparing these two groups and including only patients with R0 resections (n = 58) no significant differences in long-term survival could be shown. The following parameters were shown to have a significant or nearly significant influence on long-term survival: (1) stage of the disease: The 5-year survival of patients with stage I/II pancreatic head cancer was 63%, compared to 15% in patients with stage III/IV a + b of the disease (p = 0.0087). (2) Grading: The 1-year survival of patients with well or moderately differentiated tumors was 55%, compared to 0% for patients with poorly differentiated ductal adenocarcinoma (p = 0.0022). (3) N stage: The 5-year survival of patients in N0 stage was 46.9%, compared with 15% for N1 stage patients. The difference was not quite significant (p = 0.081). (4) Portal vein involvement: The 1-year survival was 0% in patients with R0 resections and histologically proven tumor infiltration of the portal vein, compared to 63% for patients with curative resections without portal vein involvement (p = 0.0063). In conclusion our data indicate that extensive retroperitoneal tissue clearance during pancreaticoduodenectomy for ductal pancreatic cancer does not improve survival compared to regional lymphadenectomy restricted to the right side of the mesenteric artery.

Tumour grade is one of the prognostic factors in pancreatic ductal adenocarcinoma, but its value is controversial. In this study, the predictive value and the reproducibility of the WHO grading system were reconsidered and the possibility of supplementing it with the immunohistochemically assessed proliferative activity was investigated. Seventy resected ductal adenocarcinomas of the head of the pancreas were evaluated. A total of 60 HPF fields on two to four sections per tumour were screened for glandular differentiation, mucin production, mitosis, and nuclear atypia by two observers with different degrees of experience. Each criterion was scored and the grade was calculated from the mean value of all single scores. Corresponding slides were immunohistochemically stained with the proliferation marker Ki-S5. The percentage of positive nuclei was assessed and a proliferation index (PI) assigned ( 50%=3). Multivariate analysis (Cox regression) identified grade and R stage as the most significant factors for predicting survival. The PI determined on the basis of Ki-S5 staining did not prove to be an independent prognostic factor. In 30 of 70 carcinomas, it correlated with the tumour grade. Within a given tumour grade, the cases with the least favourable prognosis could be distinguished on the basis of their PI. The inter-observer variability was considerable, with the main differences occurring in the group of G1 tumours. According to the refined WHO criteria, the histopathological grade of pancreatic ductal carcinoma is an important independent prognostic factor, but reproducibility depends on the expertise of the observer. Criteria that relate to cellular and structural differentiation seem to be more predictive than those related to proliferation. Copyright © 2000 John Wiley & Sons, Ltd.

Recent molecular studies have suggested that hyperplastic duct lesions of the pancreas are potential precursors of pancreatic ductal carcinoma. This study examines the type, distribution, age-related incidence and K-ras codon 12 mutation rate of duct lesions in the normal pancreas. Postmortem pancreases from 140 patients were screened for the presence of mucinous cell hypertrophy (MHT), ductal papillary hyperplasia (DPH), adenomatoid ductal hyperplasia (ADH), and squamous metaplasia (SQM). Microdissected cell samples were analyzed for K-ras codon 12 mutations by polymerase chain reaction amplification of exon 1 of the K-ras gene, combined with constant denaturing gel electrophoresis, and analyzed by sequencing. Of the 140 specimens 114 showed duct lesions. The lesions were evenly distributed throughout the pancreas. They were more common beyond the age of 40. MHT was present in 68%, DPH in 36%, ADH in 40%, and SQM in 36% of the cases. K-ras mutations were found in 19 samples from 15 out of 79 pancreases (18%), including all types of duct lesions and a variant of ADH with dense stroma. 67% of the K-ras-positive specimens showed the transition GGT to GAT (8) or GTT (5). Hyperplastic/metaplastic duct changes of the pancreas increase with age, but their distribution pattern in the pancreas differs from that of ductal carcinomas.

BACKGROUND Hyperplastic ductal lesions of the pancreas are believed to represent precursors of ductal adenocarcinoma. The most frequent mutation in manifest ductal carcinoma of the pancreas is the K-ras mutation at codon 12. The frequency and significance of this mutation in precursor lesions are a matter of controversy. METHODS The study included 35 resection specimens of ductal adenocarcinoma of the head of the pancreas and 3 noncancerous, noninflammatory pancreases. Ductal lesions were classified according to established criteria. Single cells from these lesions were microdissected and analyzed by the denaturing gradient gel electrophoresis polymerase chain reaction method. RESULTS All primary adenocarcinomas showed a K-ras mutation at codon 12 (25 cases with GAT, 7 cases with GTT, and 3 cases with CGT). One hundred and six of 364 ductal lesions were positive for the mutation. The highest relative percentage (53%) occurred in adenomatoid hyperplasia, followed by 36% in papillary hyperplasia, 26% in mucinous hypertrophy, and 14% in squamous metaplasia. With only two exceptions the mutation pattern of the ductal lesions and that of the corresponding primary tumor were identical. Twenty-one samples from normal ducts (17%) also harbored the K-ras mutation, as did 3 lesions from noncancerous specimens. CONCLUSIONS K-ras mutations are common events in normal, hyperplastic, metaplastic, and neoplastic pancreatic ductal cells. Because K-ras mutations frequently, although not exclusively, are related to mucinous differentiation of pancreatic cells, this mutation may not cause but only promote mucinous differentiation. The prevalence of a certain mutation pattern in nonneoplastic and neoplastic ductal cells in an individual pancreas suggests the dominance of one carcinogenic factor. Cancer 1999;85:1703–10. © 1999 American Cancer Society.

Background and Methods: Because the use of immunohistochemistry in the diagnosis of granulosa cell tumor (GCT) has not been fully explored, routinely processed (formalin-fixed, paraffin-embedded) tissue from 11 GCT, adult type, was investigated immunohistochemically (ABC method) with a broad spectrum of antibodies against various markers, including p53 and Ki-67. All of the tumors exhibited typical morphology, were limited to the ovary (stage I), and 7 cases followed a benign clinical course. Results: All the tumors exhibited strong expression of vimentin, but most other antigens (including smooth muscle actin) were expressed infrequently by a minority of tumor cells or not at all. Tumor cells in 9 GCT expressed inhibin A. All the tumors exhibited very low proliferative activity, fewer than 10% of the tumor cell nuclei being stained by the antibody MIB-1 (Ki-67 antigen). The antibody D07 revealed marked overexpression of p53 protein in only one tumor. Clinical outcome was not found to be related to immunophenotypic differences. Conclusions: The diagnosis of GCT should be based primarily on the typical morphology revealed by conventional stains, but additional immunohistochemical staining with a small panel of selected antibodies (for example, against keratin, vimentin, and inhibin A) may be helpful in a few cases. The very low proliferative activity and the lack of overexpression of p53 protein are consistent with the benign clinical behavior of the majority of GCT.

The prognosis of ductal adenocarcinoma of the pancreas is poor. Despite many attempts at a more aggressive surgical approach, tumor recurrence rates of around 80% are common. For various reasons, most of the studies on the subject are difficult to compare. Not only do the surgical techniques vary, but, more importantly, the methods used for processing the specimens and for the pathological examination differ. If we are to improve the situation, it would appear imperative to standardize procedures. Standardized pathological staging of pancreaticoduodenectomy specimens should be performed mainly with reference to the guidelines of the WHO and UICC, with optional staging of the lymph nodes according to their anatomical site. Precise definition and accurate examination of the resection margins, especially of that towards the retroperitoneum, is essential for a better comparison of the results of the different therapeutic strategies and approaches to pancreatic carcinoma.

Background: The extent of pancreatic resection and lymphadenectomy, both for Kausch-Whipple pancreatoduodenectomy and for left pancreatectomy, is variable between surgeons, according to their training. Methods: On May 30, 1998, a consensus conference on the surgical treatment of pancreatic cancer took place in Castelfranco Veneto, Italy. A group of 29 European surgeons and pathologists, recognized as international experts, analyzed the surgical and pathological procedures used in European countries to resect pancreatic cancer and examine the specimen. Results: A general agreement was reached on the definitions of ‘standard’, ‘radical’ and ‘extended radical’ Kausch-Whipple pancreatoduodenectomy for carcinoma of the head of the pancreas, and ‘standard’ and ‘radical’ left pancreatectomy for carcinoma of the body and tail of the pancreas. Segmental venous resection, as well as adjacent organ resection, can be performed at the time of standard, radical or extended radical pancreatoduodenectomy or left pancreatectomy if required. The pylorus-preserving procedure is contraindicated only for carcinomas of the anteriorsuperior part of the head of the pancreas. Guidelines for a standardized pathological examination of the resected specimen were produced. Conclusion: Adoption of the recommended terminology will improve outcome comparisons between institutions performing the different procedures. Moreover, standardization of operations, terminology and pathological reporting is essential for prospective randomized trials comparing different operations either alone or within the context of adjuvant therapy studies.

Design: It was the aim of this study to investigate the influence of extended retroperitoneal tissue clearance on long-term survival in patients with ductal adenocarcinoma of the head of the pancreas. Patients and methods: From 10/1988 to 3/1998 a prospective observation study was initiated in 108 patients with malignant growth in the head of the pancreas to compare patients with regional lymphadenectomy (RLA) versus extended retroperitoneal tissue clearance (ELA). In 36 patients other tumors than ductal adenocarcinomas were found, so that 72 patients with a partial pancreaticoduodenectomy and a histologically established diagnosis of ductal adenocarcinoma were included. Pancreaticoduodenectomy was combined with RLA in 26 cases and with ELA in 46 patients. Results: Comparing only R0-resected patients (n=58) no significant difference in long-term survival rates between the RLA and the ELA group was found. Hospital mortality was 3.8% in the RLA group and 6.5% in the ELA group. Significant or nearly significant results were shown for the following parameters: Stage of the disease: Patients after partial pancreaticoduodenectomy of a stage I/II cancer of the head of the pancreas showed a 63% 5-year survival rate compared to 15% in patients in stage III or IV (p=0.0087). Grading: No patient with a poorly differentiated ductal adenocarcinoma of the head of the pancreas survived the first year in comparison to 55% of patients with well or moderately differentiated tumors (p=0.0022). N-stage: 5-year survival of patients in NO stage was 46.9% and 15% for NI stage patients (p=0.081). Portal vein infiltration: No patient with a RO-resection and histologically proven tumor infiltration of the portal vein survived the first year whereas 63% of patients did so after curative resection without portal vein involvement (p=0.0063). Conclusion: Out data indicate that extensive retroperitoneal tissue clearance does not improve long-term survival rates compared to regional lymphadenectomy restricted to the right side of the mesenteric artery.

Pancreatic cancer is still one of the most difficult cancers to cure. In Denmark about 700 cases are diagnosed every year [1]. Reports on the 5-year survival among patients with pancreatic ductal a...

Introduction: Pancreatic adenocarcinomas are largely resistant to apoptosis. More than 50% of pancreatic tumors reveal mutations in the p53 tumor suppressor gene. Methods: We investigated the growth of pancreatic tumor cells after downregulation of p53 protein expression by antisense oligodeoxynucleotides. Results: Proliferation and p53 expression of PancTu-I cells overexpressing mutant p53 protein were inhibited by antisense oligodeoxynucleotide treatment. When analyzed, two of three other pancreatic tumor cell lines with mutated p53 were also inhibited in their growth. Two of two wild-type (wt) p53 pancreatic tumor cells were not significantly influenced by p53 expression and were, only to a lesser extent, affected in their proliferation. K562 cells (lacking p53 mRNA) and normal human skin fibroblasts used as a target mismatch control showed no changes in proliferation rates with treatment. The different biological effects in the various cells were not caused by differences in the uptake of the oligodeoxynucleotides as monitored by confocal laser-scanning microscopy. Conclusions: Truncation and 5′- and 3′-lipophilic modifications of the oligodeoxynucleotides drastically enhanced the growth inhibition of PancTu-I cells, which were resistant to apoptosis-inducing agents. Furthermore, a higher sequence-specificity of the observed effects was achieved with these compounds.

Nichtepitheliale maligne Tumoren des Pankreas sind mit einer Haufigkeit von ∼0,6% eine Raritat unter Pankreasneoplasien. Sie werden immer unter der Verdachtsdiagnose eines Pankreaskarzinoms exploriert. Von uber 600 primaren Pankreasneoplasien des vorliegenden Pankreastumorarchivs waren lediglich 5 Malignome nichtepithelialer Genese: ein maligner peripherer Nervenscheidentumor [MPNST], ein Leiomyosarkom, ein malignes Mesotheliom, 2 periphere neuroektodermale Tumoren [PNET]. Die Differentialdiagnose umfast eine sekundare Infiltration des Pankreas durch mesenchymale Tumoren des Retroperitoneums, undifferenzierte Pankreaskarzinome und speziell fur den PNET maligne Lymphome. Durch eine praoperative Chemotherapie und Downstaging kann im Falle des PNET Operabilitat und eine Verbesserung der Prognose erzielt werden.

Zystische Lasionen des Pankreas stellen wie kaum eine andere Veranderung im Pankreas eine morphologisch extrem heterogene Gruppe von Veranderungen dar mit einer erheblichen prognostischen Relevanz von benignem Verlauf mit Wait-and-see-Strategie bis zu rasch progredienten Verlaufen mit letalem Ausgang. Haufigkeitsangaben variieren zwischen 1 % und 15 %. Mit der verbesserten Bildgebung nimmt die Zahl an kleineren zystischen Lasionen zu. Von besonderer Wichtigkeit ist die histologische Unterscheidung zwischen dem serosen und dem duktal-muzinosen Phanotyp (serose Neoplasie und intraduktal-papillare muzinose Neoplasie und muzinos-zystische Neoplasie). Die klinisch-pathologische Korrelation einer Beteiligung des Hauptgangs oder nur der Seitengange ist von groser prognostischer und therapeutischer Relevanz. Eine gemeinsame interdisziplinare Therapiebesprechung sollte fur jeden Patienten mit einer zystischen, klinisch relevanten Pankreaslasion angestrebt werden.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6 mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

Leiomyosarcoma (LMS) accounts for approximately 7% of all soft tissue sarcomas and occurs most frequently in the gastrointestinal tract and uterus. LMS of the nasal cavity and paranasal sinuses are rare and only about 40 cases of LMS of the nose and paranasal sinuses have been reported in the literature. A further case of LMS of the right turbinate is presented, treated twice by surgery. To date, the patient has been free of disease for more than 48 months. The symptoms, pathology, treatment and prognosis, and origin of this tumor are discussed. Initially, LMS should be treated by extensive surgical excision, but long-term follow-up is essential due to the high rate of local recurrence. Radiotherapy and chemotherapy are insufficient therapeutic approaches. Frequency of recurrence and prognosis depend on the tumor site. The prognosis of LMS of the nasal cavity is better than LMS of the paranasal sinuses.

Between September 1991 and December 1993, 253 patients were operated on using the Classical Intrafascial SEMM (Serrated Edged Macro Morcellator) Hysterectomy (CISH) technique. One hundred fifty-two patients were assigned to pelviscopic CISH and 101 to laparotomic CISH. Uterine leiomyomas with menstrual disorders and pressure symptoms topped the list of indications with 61%. In all cases, initially transuterine mucosal resection and coring of the cervicouterine cylinder were carried out followed by the intrafascial supracervical dissection of the uterus. The size of the uterus played a decisive role in selecting the cases for CISH technique either by pelviscopy or laparotomy. The cervicouterine mucosal cylinders were cored using the Calibrated Uterine Resection Tool (CURT). Cervical thickness and diameters were measured preoperatively by transvaginal sonography for facilitating the use of a specific-sized CURT. After removal of this cylinder, hemostasis in the area was secured by coagulating with an endocoagulation device. The advantage of this technique is that the pelvic floor integrity remains intact, and because uterine arteries and ureters were not touched, the so called “complication zone” is thus avoided.The histological findings are in agreement with the indications, the leiomyomas and leiomyomas with adenomyosis being the most frequent pathology. The histologic analysis showed that in all cases the squamocolumnar transformation zone was totally removed. There were 11 (4.4%) complications, promptly identified and treated without further problems.The value of the Classical intrafascial supracervical hysterectomy without colpotomy including the resection of transformation zone speaks for itself, because there is less physical stress and recovery is quick. However, it has yet to prove its value as compared with other techniques for hysterectomy for specific indications.

Study Objective. To evaluate the classic intrafascial SEMM (serrated-edge macromorcellated) hysterectomy (CISH) performed by pelviscopy and by laparotomy, and determine the histologic features of the procedures. Design. The first 253 women who required hysterectomy were assigned to undergo the procedure by pelviscopy or laparotomy based on uterine size. Patients. One hundred fifty-two women underwent CISH by pelviscopy and 101 by laparotomy. Interventions: Between September 1991 and December 1993, the patients underwent the two procedures. Uterine leiomyomas with menstrual disorders and pressure symptoms were the principal indications (61%). Measurements and Main Results. Histologic findings were in agreement with indications for the procedures. Leiomyomas and leiomyomas with adenomyosis were the most frequent findings. Histologic analysis revealed that the squamocolumnar transformation zone was totally removed in all cases, and all cervical glands were excised in 92%. Conclusion. Cervical dysplasia is not a contraindication to CISH, but emphasizes the importance of adequate preoperative screening. This is a conservative operation that may protect against some cervical cancers.

Vaginal papillomata are rare, particularly in children. The macroscopic appearance is suggestive of a botryoid rhabdomyosarcoma, which is more common in this age group. The histogenesis of these tumors is still controversial, the choices being mesonephric or Müllerian origin. In our case cytokeratins and intermediate filaments were looked for immunohistochemically. Squamous epithelium as well as the cylindrical epithelium expresses type I cytokeratins, an acidic polypeptide typical of cylindrical epithelium. A strong expression of EMA in both epithelial types and CEA staining of the cylindrical epithelium support the hypothesis that these papillomata derive from Müllerian epithelium. Recurrence as observed in our case has not been described before. Treatment involves the simple removal of the papilloma.

The present study attempts to confirm the effectiveness of a new method of pelviscopic hysterectomy which maintains the pelvic floor integrity comparable to that in a supracervical uterus amputation. A major advantage of this procedure is that the central portion of the cervix and transformation zone is punched out using a special resection tool for the purpose of removing any potential source of cancer. Thirty-four specimens resected by pelviscopic hysterectomy were investigated using histological giant and serial sections. Morphometrical analysis was performed using MOP-AM02 (Kontron Instruments). The transitional zone and cervical glands were excised completely with an average security distance of 1.5 cm to the resection margins. No mesonephric remnants were found which might serve as a possible source of adenocarcinoma. Our study confirms that the application of this new technique of pelviscopic hysterectomy is not limited by the development of stump carcinoma while also possessing the additional advantage of maintaining pelvic floor integrity.

Establishing a gene expression profile of defined subtypes of cells within an organ is still challenging because it frequently requires microdissection and subsequent amplification of the limited amount of messenger RNA (mRNA) isolated from the microdissected tissue in order to be able to proceed with comprehensive gene expression analyses via microarray or serial analysis of gene expression (SAGE) technology. Here we describe a manual microdissection strategy for the isolation of high-quality RNA. Furthermore, a strategy for combining linear amplification of RNA with longSAGE is described that allows the use of antisense RNA (aRNA) generated via the well-established linear amplification of RNA procedure together with the conventional SAGE or longSAGE technology.

To increase the knowledge about the development of pancreatic ductal adenocarcinoma, (PDAC) detailed analysis of the tumor progression is required. To identify proteins differentially expressed in the pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of PDAC, we conducted a quantitative proteome study on microdissected PanIN cells. Proteins from 1000 microdissected cells were subjected to a procedure combining fluorescence dye saturation labeling with high resolution two-dimensional gel electrophoresis (2-DE). Differentially regulated protein spots were identified using protein lysates from PDAC tissues as a reference proteome followed by nanoLC-ESI-MS/MS. Thirty-seven single lesions of different PanIN grade (PanIN 1A/B, PanIN 2, PanIN 3) from nine patients were analyzed. Their protein expression was compared with each other, with PDAC cells and with normal ductal cells. The differential expression of differentially regulated protein spots was validated by means of immunohistochemistry using tissue microarrays. Of 2500 protein spots, 86 were found to be significantly regulated (p0.05, ratio1.6) during PanIN progression. Thirty-one nonredundant proteins were identified by mass spectrometry. Immunohistochemistry revealed that the differential expression of the selected candidate proteins major vault protein (MVP), anterior gradient 2 (AGR 2) and 14-3-3 sigma, annexin A4, and S100A10 could be successfully validated in PanIN lesions. The highly sensitive and robust proteome analysis revealed differentially regulated proteins involved in pancreatic tumor progression. The analysis of normal preneoplastic and neoplastic pancreatic tissue establishes a basis for identification of candidate biomarkers in PanIN progression that can be detected in pancreatic juice and in serum or are candidates for in vivo imaging approaches.

Establishing a gene expression profile of defined subtypes of cells within an organ is still challenging because it frequently requires microdissection and subsequent amplification of the limited amount of messenger RNA (mRNA) isolated from the microdissected tissue in order to be able to proceed with comprehensive gene expression analyses via microarray or serial analysis of gene expression (SAGE) technology. Here we describe a manual microdissection strategy for the isolation of high-quality RNA. Furthermore, a strategy for combining linear amplification of RNA with longSAGE is described that allows the use of antisense RNA (aRNA) generated via the well-established linear amplification of RNA procedure together with the conventional SAGE or longSAGE technology.

Background: MicroRNAs (miRNAs) are RNA molecules that are involved in the regulation of many cellular processes, including those related to human cancers. The aim of this study was to determine, as a proof of principle, whether specific candidate miRNAs could be detected in fine-needle aspirate (FNA) biopsies of pancreatic ductal adenocarcinoma (PDAC) and could accurately differentiate malignant from benign pancreatic tissues. Methods: We used TaqMan® assays to quantify miRNA levels in FNA samples collected in RNARetain (n = 16) and compared the results with a training set consisting of frozen macrodissected pancreatic samples (n = 20). Results: Quantitative reverse-transcription PCR analysis confirmed that miRNA levels are affected in PDAC FNAs and correlate well with the changes observed in the training set of frozen pancreatic samples. Analysis of the amounts produced for a few specific miRNAs enabled identification of PDAC samples. The combination of miR-196a and miR-217 biomarkers further improved the ability to distinguish between healthy tissue, PDAC, and chronic pancreatitis in the training set (P = 8.2 × 10−10), as well as segregate PDAC FNA samples from other FNA samples (P = 1.1 × 10−5). Furthermore, we showed that miR-196a production is likely specific to PDAC cells and that its incidence paralleled the progression of PDAC. Conclusions: To the best of our knowledge, this study is the first to evaluate the diagnostic potential of miRNAs in a clinical setting and has shown that miRNA analysis of pancreatic FNA biopsy samples can aid in the pathologic evaluation of suspicious cases and may provide a new strategy for improving the diagnosis of pancreatic diseases.

Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia. (Cancer Res 2006; 66(1): 95-106)

In order to identify new molecular markers for pancreatic intra-epithelial neoplasias (PanINs), the precursor lesions of pancreatic ductal adenocarcinoma, we established a proteomics approach analysing microdissected PanIN cells. Due to the limited amount of proteins available from microdissection, we developed a procedure including fluorescence dye saturation labelling in combination with high resolution two-dimensional gel electrophoresis. With this procedure we were able to analyse proteins extracted from 1000 microdissected cells with a high resolution of up to 2500 protein spots. Using protein lysates from the pancreatic carcinoma tissue as a reference proteome, we were able to successfully identify the proteins. Thus, we could match approximately 2200 protein spots (92%) of the microdissected sample proteome to the reference proteome for protein identification using matrix-assisted laser desorption/ionisation-time of flight mass spectrometry and nanoliquid chromatography-electrospray ionisation tandem mass spectrometry after in-gel digestion. The first proteome analysis of microdissected PanIN-2 grades revealed eight differentially expressed proteins. The differential expression of the three actin filament-associated proteins – transgelin, vimentin and MRCL3 as well as actin itself – indicates a relevant role of the actin cytoskeleton during pancreatic tumour progression. Additionally, two members of the annexin family (annexin A2 and A4) implicate a functional contribution of exocytotic and endocytotic pathways at that stage.